The proposed project focuses on developing a novel oral delivery system for exenatide and insulin for the treatment of Type 2 Diabetes. Both exenatide and insulin suffer from the limitations of enzymatic degradation in the gastrointestinal tract and poor oral bioavailability, thus requiring administration via subcutaneous injections. The proposed novel oral delivery system for exenatide utilizes multilayered, millimeter-sized mucoadhesive patches, which are enclosed in an enteric-coated capsule so as to prevent dissolution of the capsule in the stomach. Upon entering the intestine, the capsule dissolves to release patches in the intestinal lumen, where the patches adhere to the intestinal mucosa due to their mucoadhesive nature and slowly release exenatide and insulin into the blood stream. The specific aims of the project are designed as follows: 1. Design and Characterization of Mucoadhesive Patches: We will prepare mucoadhesive patches by compressing optimal blends of mucoadhesive polymers into disks of 2-4 mm diameter and 400 m thickness, and coating them on three sides by a 50 m thick layer of an impermeable layer comprising ethylcellulose. Patches will be tested for their ability to induce high mucoadhesion, unidirectiona as well as sustained release of peptides from the open face for 5-6 hours, and protection of peptides from the digestive enzymes in the intestine. 2. Assessment of Peptide Transport, and Protection against Degradation: We will assess the ability of patches to deliver exenatide and insulin across co-cultures of Caco-2 and mucus producing goblet cell sub-line HT29-MTX. We will also assess the ability of select penetration enhancers to enhance peptide transport across the intestine. Interactions of mucoadhesive patches with water soluble intestinal mucins will be studied in vitro so as to understand the ability of the patches to withstand the physiological hurdles to adhesion and absorption following oral ingestion. Long-term stability of patches will also be tested. 3. Assessment of In vivo Pharmacokinetic and Pharmacodynamic Efficacy, and Safety of Mucoadhesive Patches in Rats and Miniature Swine. Using Sprague Dawley rats as an animal model, we will assess the ability of patches to deliver therapeutic doses of exenatide and insulin after direct jejunal administration as well as oral administration from a patch-carryin capsule. Pharmacokinetic and pharmacodynamic analysis of exenatide and insulin delivery will be performed. Toxicity of patches will be assessed by histological evaluation. Following initial studies in rats, we will test the optimized formulations for pharmacokinetic profile in miniature swine for insulin as well as exenatide. Toxicological studies will also be performed in miniature swine after multiple doses.